Scientists at the University of California, Davis (UC Davis) have published a paper that could turn the current understanding of how psychedelics work on its head.
For a long time, it was believed that psychedelics activated the serotonin (5-HT)2A receptor class on the surface of neurons (brain cells). These receptors are present throughout the brain, and their activation by psychedelics was thought to cause the powerful hallucinations associated with these substances.
However, if these compounds are activating serotonin receptors already present in the brain, why doesn’t serotonin promote the growth of new brain cells and cause us to hallucinate?
To answer this question, the researchers at UC Davis looked inside neurons and found that it is actually through the activation of receptors inside the cell that psychedelics exert their effects.
The researchers concluded that, rather than serotonin, the natural activator of these intracellular receptors is likely to be another molecule, potentially N,N-dimethyltryptamine (DMT), which is found in the Amazonian psychedelic drink Ayahuasca as well as the human brain. Psilocybin from magic mushrooms is also very similar to DMT in terms of molecular structure.
The findings could explain why different psychedelics have different effects on neuroplasticity and mood, as well as open up the possibility of improved drug-delivery techniques.
It also raises the question of whether psychedelics should replace serotonin-targeting medicines like SSRI antidepressants, which work by increasing levels of serotonin in the brain
Scientists already know that substances like MDMA, DMT, and psilocybin hold great promote in treating mental health conditions like depression. What this study adds is new insight into how these compounds work in the brain and why they may help patients.
The study aimed to understand the neuroplastic effects of psychedelics and investigate whether a stronger binding to extracellular (outer-cell) 5-HT2A receptors resulted in more extreme neuroplasticity.
However, the team found that there was no such relationship, and a compound’s ability to cross cell membranes was positively related to its neuroplastic effects.
To determine this, the team modified the structure of two common psychedelics – DMT and psilocin – and a chemical (ketanserin) often used to block psychedelic activity, all of which could permeate the cell membrane but not promote neurogenesis.
However, when these modified psychedelics were added to electroporated cells, which create tiny holes in the cellular membrane that permit molecules’ entry into the cell’s interior, they were suddenly capable of producing plasticity in the same way as their unmodified counterparts.
The team also found that electroporation significantly improved the delivery of drugs to target intracellular receptors, which could have significant implications for drug development and delivery.
In conclusion, the study revealed that it is receptors inside the cell, not on the surface, that are activated by psychedelics to stimulate the growth of brain cells and produce antidepressant effects.
This suggests that serotonin may not be the natural activator of a considerable portion of 5HT2A receptors, and the researchers think that DMT is more likely.
The findings could pave the way for new drug development and delivery strategies by improving the delivery of drugs to target intracellular receptors.
A commentary published alongside the study noted: “These findings are an important step forward for a rapidly expanding and much-needed field of study.”
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